Sequestosome 1

Sequestosome-1 is a protein that in humans is encoded by the SQSTM1 gene.^[5][6][7] Also known as the ubiquitin-binding protein p62,^[8] it is an autophagosome cargo protein that targets other proteins that bind to it for selective autophagy. By interacting with GATA4 and targeting it for degradation, it can inhibit GATA-4 associated senescence and senescence-associated secretory phenotype.^[9]

SQSTM1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1Q02, 2JY7, 2JY8, 2K0B, 2KNV, 4MJS, 4UF8, 4UF9
Identifiers
Aliases	SQSTM1, A170, OSIL, PDB3, ZIP3, p60, p62, p62B, FTDALS3, Sequestosome 1, NADGP, DMRV
External IDs	OMIM: 601530; MGI: 107931; HomoloGene: 31202; GeneCards: SQSTM1; OMA:SQSTM1 - orthologs
Gene ___location (Human) Chr. Chromosome 5 (human)[1] Band 5q35.3 Start 179,806,398 bp[1] End 179,838,078 bp[1]
Gene ___location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 B1.3 Start 50,090,193 bp[2] End 50,101,654 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right adrenal cortex left adrenal gland left adrenal cortex stromal cell of endometrium muscle of thigh right lobe of thyroid gland left lobe of thyroid gland gallbladder gastric mucosa Descending thoracic aorta Top expressed in dentate gyrus of hippocampal formation granule cell muscle of thigh right kidney triceps brachii muscle adrenal gland ventromedial nucleus superior frontal gyrus temporal muscle central gray substance of midbrain sternocleidomastoid muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity receptor tyrosine kinase binding zinc ion binding SH2 ___domain binding metal ion binding protein serine/threonine kinase activity K63-linked polyubiquitin modification-dependent protein binding protein binding identical protein binding protein kinase binding protein kinase C binding ubiquitin binding enzyme binding ubiquitin protein ligase binding ionotropic glutamate receptor binding Cellular component cytoplasm endosome PML body late endosome P-body phagophore assembly site nucleoplasm aggresome autophagosome amphisome endoplasmic reticulum inclusion body lysosome sperm midpiece extracellular exosome cytoplasmic vesicle nucleus cytosol intracellular membrane-bounded organelle autolysosome mitochondrion sarcomere Lewy body Biological process apoptotic process protein localization cell differentiation positive regulation of protein phosphorylation intracellular signal transduction ubiquitin-dependent protein catabolic process regulation of mitochondrion organization protein heterooligomerization immune system process response to stress regulation of Ras protein signal transduction negative regulation of apoptotic process autophagy endosomal transport regulation of protein complex stability autophagy of mitochondrion positive regulation of apoptotic process regulation of I-kappaB kinase/NF-kappaB signaling positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II protein phosphorylation mitophagy response to mitochondrial depolarisation macroautophagy endosome organization protein localization to perinuclear region of cytoplasm response to ischemia mitochondrion organization aggrephagy selective autophagy interleukin-1-mediated signaling pathway positive regulation of long-term synaptic potentiation positive regulation of protein localization to plasma membrane Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8878 18412 Ensembl ENSG00000161011 ENSG00000284099 ENSMUSG00000015837 UniProt Q13501 Q64337 RefSeq (mRNA) NM_001142298 NM_001142299 NM_003900 NM_001290769 NM_011018 RefSeq (protein) NP_001135770 NP_001135771 NP_003891 NP_001277698 NP_035148 Location (UCSC) Chr 5: 179.81 – 179.84 Mb Chr 11: 50.09 – 50.1 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Mutations in SQSTM1 are a common cause of Paget's disease of bone.^[10]

Interactions

Sequestosome 1 has been shown to interact with:

• MAP1LC3A,^[11]
• PRKCI,^[12]
• RAD23A,^[13]
• RIPK1,^[14]
• TRAF6^[15]
• TrkA,^{[16][17][18][19]} and
• TrkB.^[17][18]
• Nrf2^[20]

Role in cancer

The SQSTM1 gene, which is actively transcribed as part of normal cellular function, is sometimes identified in fusion proteins, which can cause cancer when SQSTM1 is abnormally fused to a tyrosine kinase or other pro-proliferation gene. These genes are normally tightly regulated, but when bound to a minimally regulated gene like SQSTM1, they cause abnormal over-expression.^[21]

References

1. ENSG00000284099 GRCh38: Ensembl release 89: ENSG00000161011, ENSG00000284099 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000015837 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Joung I, Strominger JL, Shin J (July 1996). "Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 ___domain". Proceedings of the National Academy of Sciences of the United States of America. 93 (12): 5991–5995. Bibcode:1996PNAS...93.5991J. doi:10.1073/pnas.93.12.5991. PMC 39176. PMID 8650207.
6. Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathanson EC, Kieff E, et al. (February 1996). "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes". Journal of Virology. 70 (2): 1143–1153. doi:10.1128/JVI.70.2.1143-1153.1996. PMC 189923. PMID 8551575.
7. "Entrez Gene: SQSTM1 sequestosome 1".
8. Online Mendelian Inheritance in Man (OMIM): 601530
9. Cassidy LD, Narita M (Sep 2015). "GATA get a hold on senescence" (PDF). Science. 349 (6255). New York, N.Y.: 1448–1449. Bibcode:2015Sci...349.1448C. doi:10.1126/science.aad2501. PMID 26404812. S2CID 35805331.
10. Layfield R, Ciani B, Ralston S, Hocking L, Sheppard P, Searle M, et al. (2004-10-26). "Structural and functional studies of mutations affecting the UBA ___domain of SQSTM1 (p62) which cause Paget's disease of bone". Biochemical Society Transactions. 32 (Pt 5): 728–730. doi:10.1042/bst0320728. ISSN 0300-5127. PMID 15493999. S2CID 22544044.
11. Shvets E, Fass E, Scherz-Shouval R, Elazar Z (August 2008). "The N-terminus and Phe52 residue of LC3 recruit p62/SQSTM1 into autophagosomes". Journal of Cell Science. 121 (Pt 16): 2685–2695. doi:10.1242/jcs.026005. PMID 18653543. S2CID 2782335.
12. Sanchez P, De Carcer G, Sandoval IV, Moscat J, Diaz-Meco MT (May 1998). "Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62". Molecular and Cellular Biology. 18 (5): 3069–3080. doi:10.1128/mcb.18.5.3069. PMC 110686. PMID 9566925.
13. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
14. Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J (Jun 1999). "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation". The EMBO Journal. 18 (11): 3044–3053. doi:10.1093/emboj/18.11.3044. PMC 1171386. PMID 10356400.
15. Sanz L, Diaz-Meco MT, Nakano H, Moscat J (April 2000). "The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway". The EMBO Journal. 19 (7): 1576–1586. doi:10.1093/emboj/19.7.1576. PMC 310227. PMID 10747026.
16. Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J (March 2001). "The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor". Journal of Biological Chemistry. 276 (11): 7709–7712. doi:10.1074/jbc.C000869200. PMID 11244088.
17. Geetha T, Wooten MW (February 2003). "Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling". Journal of Biological Chemistry. 278 (7): 4730–4739. doi:10.1074/jbc.M208468200. PMID 12471037.
18. Jadhav T, Geetha T, Jiang J, Wooten MW (Jul 2008). "Identification of a consensus site for TRAF6/p62 polyubiquitination". Biochemical and Biophysical Research Communications. 371 (3): 521–524. Bibcode:2008BBRC..371..521J. doi:10.1016/j.bbrc.2008.04.138. PMC 2474794. PMID 18457658.
19. Wooten MW, Geetha T, Babu JR, Seibenhener ML, Peng J, Cox N, et al. (March 2008). "Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins". Journal of Biological Chemistry. 283 (11): 6783–6789. doi:10.1074/jbc.M709496200. PMID 18174161.
20. Feng, Lifeng et al. “Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia” Theranostics vol. 7,7 1890-1900. 10 Apr. 2017, doi:10.7150/thno.19135
21. Badiu DC, Ploscaru IC, Zgura A, Bacinschi X, Smarandache CG, Serban D, et al. (July 2022). "A review of NTRK fusions in cancer". Annals of Medicine and Surgery. 79: 103893. doi:10.1016/j.amsu.2022.103893. ISSN 2049-0801. PMC 9289232. PMID 35860155.

Further reading

• Geetha T, Wooten MW (Feb 2002). "Structure and functional properties of the ubiquitin binding protein p62". FEBS Letters. 512 (1–3): 19–24. Bibcode:2002FEBSL.512...19G. doi:10.1016/S0014-5793(02)02286-X. PMID 11852044. S2CID 22029085.
• Layfield R, Ciani B, Ralston SH, Hocking LJ, Sheppard PW, Searle MS, et al. (Nov 2004). "Structural and functional studies of mutations affecting the UBA ___domain of SQSTM1 (p62) which cause Paget's disease of bone". Biochemical Society Transactions. 32 (Pt 5): 728–730. doi:10.1042/BST0320728. PMID 15493999. S2CID 22544044.
• Michou L, Collet C, Laplanche JL, Orcel P, Cornélis F (May 2006). "Genetics of Paget's disease of bone". Joint Bone Spine. 73 (3): 243–248. doi:10.1016/j.jbspin.2005.05.009. PMID 16574459.
• Park I, Chung J, Walsh CT, Yun Y, Strominger JL, Shin J (Dec 1995). "Phosphotyrosine-independent binding of a 62-kDa protein to the src homology 2 (SH2) ___domain of p56lck and its regulation by phosphorylation of Ser-59 in the lck unique N-terminal region". Proceedings of the National Academy of Sciences of the United States of America. 92 (26): 12338–12342. doi:10.1073/pnas.92.26.12338. PMC 40352. PMID 8618896.
• Iyer N, Reagan MS, Wu KJ, Canagarajah B, Friedberg EC (Feb 1996). "Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein". Biochemistry. 35 (7): 2157–2167. doi:10.1021/bi9524124. PMID 8652557.
• Vadlamudi RK, Joung I, Strominger JL, Shin J (Aug 1996). "p62, a phosphotyrosine-independent ligand of the SH2 ___domain of p56lck, belongs to a new class of ubiquitin-binding proteins". Journal of Biological Chemistry. 271 (34): 20235–20237. doi:10.1074/jbc.271.34.20235. PMID 8702753.
• Marcus SL, Winrow CJ, Capone JP, Rachubinski RA (Nov 1996). "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor". Journal of Biological Chemistry. 271 (44): 27197–27200. doi:10.1074/jbc.271.44.27197. PMID 8910285.
• Jallal B, Mossie K, Vasiloudis G, Knyazev P, Zachwieja J, Clairvoyant F, et al. (May 1997). "The receptor-like protein-tyrosine phosphatase DEP-1 is constitutively associated with a 64-kDa protein serine/threonine kinase". Journal of Biological Chemistry. 272 (18): 12158–12163. doi:10.1074/jbc.272.18.12158. PMID 9115287.
• Sanchez P, De Carcer G, Sandoval IV, Moscat J, Diaz-Meco MT (May 1998). "Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62". Molecular and Cellular Biology. 18 (5): 3069–3080. doi:10.1128/mcb.18.5.3069. PMC 110686. PMID 9566925.
• Vadlamudi RK, Shin J (Sep 1998). "Genomic structure and promoter analysis of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein". FEBS Letters. 435 (2–3): 138–142. Bibcode:1998FEBSL.435..138V. doi:10.1016/S0014-5793(98)01021-7. PMID 9762895. S2CID 3184369.
• Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J (Jun 1999). "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation". The EMBO Journal. 18 (11): 3044–3053. doi:10.1093/emboj/18.11.3044. PMC 1171386. PMID 10356400.
• Stumptner C, Heid H, Fuchsbichler A, Hauser H, Mischinger HJ, Zatloukal K, et al. (Jun 1999). "Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. Demonstration of p62 as major constituent". The American Journal of Pathology. 154 (6): 1701–1710. doi:10.1016/S0002-9440(10)65426-0. PMC 1866621. PMID 10362795.
• Sudo T, Maruyama M, Osada H (Mar 2000). "p62 functions as a p38 MAP kinase regulator". Biochemical and Biophysical Research Communications. 269 (2): 521–525. Bibcode:2000BBRC..269..521S. doi:10.1006/bbrc.2000.2333. PMID 10708586.
• Sanz L, Diaz-Meco MT, Nakano H, Moscat J (Apr 2000). "The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway". The EMBO Journal. 19 (7): 1576–1586. doi:10.1093/emboj/19.7.1576. PMC 310227. PMID 10747026.
• Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J (Mar 2001). "The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor". Journal of Biological Chemistry. 276 (11): 7709–7712. doi:10.1074/jbc.C000869200. PMID 11244088.
• Kuusisto E, Salminen A, Alafuzoff I (Jul 2001). "Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies". NeuroReport. 12 (10): 2085–2090. doi:10.1097/00001756-200107200-00009. PMID 11447312. S2CID 21272705.
• Laurin N, Brown JP, Lemainque A, Duchesne A, Huot D, Lacourcière Y, et al. (Sep 2001). "Paget disease of bone: mapping of two loci at 5q35-qter and 5q31". American Journal of Human Genetics. 69 (3): 528–543. doi:10.1086/322975. PMC 1235483. PMID 11473345.
• Chang S, Kim JH, Shin J (Jan 2002). "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4-induced PKCzeta inhibition". FEBS Letters. 510 (1–2): 57–61. Bibcode:2002FEBSL.510...57C. doi:10.1016/S0014-5793(01)03224-0. PMID 11755531. S2CID 85579338.
• Feng L, Li J, Yang L, Zhu L, Huang X, Zhang S, et al. (2017). "Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia". Theranostics. 7 (7): 1890–1900. doi:10.7150/thno.19135. PMC 5479276. PMID 28638475.